With recent advances in animal models of disease, there has been great interest in capabilities for high-resolution ultrasound imaging. High-resolution ultrasound imaging is performed at high frequencies, typically greater than 15 MHz, whereas clinical ultrasound imaging is typically in the 1-15 MHz range. Higher frequencies are proportional to higher resolution.
High-frequency ultrasound is a popular modality for imaging animal models of human disease because of its portability, relatively low cost, and real-time imaging capability. High frequency ultrasound (>15 MHz) is different from traditional clinical ultrasound because of its high resolution capability, although with the sacrifice of penetration depth. Encapsulated microbubbles are often implemented as contrast agents during these ultrasound studies to improve detection of blood flow. Their use requires an intravascular injection of a solution of microbubbles immediately prior to an imaging exam. After their injection, the microbubble contrast agents (MCAs) traverse the circulatory system with similar rheology to erythrocytes. The acoustic impedance mismatch between MCA gas cores and the surrounding blood and tissue is significant—approximately four orders of magnitude—causing them to scatter ultrasound and thus enhance the image intensity in their vicinity extremely efficiently.
The most basic method of microbubble contrast enhanced ultrasound relies on receiving the acoustic signal scattered from them at the fundamental imaging frequency. One limitation to this detection method is that echoes from both tissue and MCAs are in the same frequency band. This necessitates a large quantity of injected MCAs to compete with the inherent and unwanted tissue backscatter. However, owing to the broadband and nonlinear acoustic responses of these gas-filled spheres it is possible to overcome this limitation with other detection strategies. The most powerful MCA imaging methods are derived from their nonlinear responses to ultrasound, providing MCAs distinct differences in their echo signatures when compared to the linear responses of tissue and blood. Imaging modes such as subharmonic imaging, and phase inversion exploit MCAs' nonlinear response and provide improved contrast-to-tissue ratios compared to the previously described fundamental mode imaging. Although these nonlinear imaging methods are now widely utilized in commercial ultrasound systems operating in the 1-15 MHz range, they have yet to be implemented efficiently in high frequency ultrasound systems. One likely reason for this is that optimal MCA response requires excitation near the resonant frequency, which is typically in the 0.5-8 MHz range for bubbles of several microns in diameter and the range in which most commonly available commercially produced MCAs fall.
The ability to detect small numbers of contrast agents in a tissue background is particularly important for molecular imaging or perfusion imaging. MCAs are unique in that they scatter ultrasound energy at higher and lower harmonics than the fundamental imaging frequency. These broadband harmonics, due to the contrast agents' nonlinear response, have been shown to be most intense when insonified near the MCAs' resonant frequencies. To date, efficiently exciting harmonic response has not been possible with high-frequency imaging systems since most contrast agents are resonant in the 1-5 MHz frequency range.
Thus, there exists a need for systems which can excite microbubble contrast agents efficiently, and also detect them with a high-frequency system for high-resolution imaging.
Additionally, there has been an interest in the application of ultrasound to enhance drug and gene delivery. There are several mechanisms whereby this might occur. One mechanism is the use of radiation force (RF) to enhance both diagnostic and therapeutic ultrasound (US) imaging studies. RF pulses have shown to enhance adhesion of targeted MCAs, thus improving their signal to noise ratio. RF has also been shown to be effective in concentrating therapeutic delivery vehicles at desired locations as determined by the ultrasound focus, thereby providing a mean for ultrasound-directed, site-specific drug delivery. The magnitude of RF on MCAs is maximized when generated near their resonance frequency, typically in the 1-5 MHz range. Traditional high frequency imaging transducers are therefore not optimized to produce RF on most MCAs.
Thus, there exists a need to simultaneously image with high resolution (high frequency), and use low frequency energy to produce radiation force at the desired site, as selected by imaging.
In addition, ultrasound can mediate local drug delivery by disrupting drug-carrier vehicles, causing enhanced release of contents. Low frequency ultrasound has also been shown to locally increase vascular or cell membrane permeability, and to enhance gene transfection. These abilities are of particular interest for small animal studies, where much of the work in US molecular imaging and therapeutic delivery is being tested. However, all of these effects have been shown to occur primarily at low frequencies, typically in the 1-2 MHz range. Thus, it is not possible to mediate these therapeutic effects with a standard high frequency transducer.
Accordingly, in light of these disadvantages associated with conventional ultrasonic imaging systems, there exists a need for systems, methods, and computer readable media for high-frequency contrast imaging and image-guided therapeutics.